Use of a Blood-Flow Decrease Preventing Agent in Conjunction With Insufflating Gas

ABSTRACT

A blood-flow decrease preventing agent is used to negate or reduce the decreased oxygen delivery in abdominal organs caused by insufflating gas. Preferably a gas is delivered into the abdominal cavity consisting essentially of the insufflating gas and the blood-flow decrease preventing agent. Very preferably, a gas is used consisting essentially of carbon dioxide as the insufflating gas and ethyl nitrite as the blood-flow to abdominal organ decrease preventing agent.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/975,136, filedOct. 16, 2007, which is a continuation of U.S. Ser. No. 10/714,980,filed Nov. 18, 2003, which in turn is a division of U.S. Ser. No.09/919,931, filed Aug. 2, 2001, now U.S. Pat. No. 6,676,855. Thecontents of each of these applications are hereby incorporated byreference in their entireties.

TECHNICAL FIELD

This invention is directed at negating or reducing decrease inblood-flow to abdominal organs which would otherwise have decreasedoxygen delivery because of being contacted with an insufflating gas,typically carbon dioxide.

BACKGROUND OF THE INVENTION

In laparoscopic surgery or diagnosis, the insufflating gas used normallyis carbon dioxide. However, the carbon dioxide pneumoperitoneumdecreases blood-flow to abdominal organs, and this can result inelevated liver functions, decreased renal perfusion, hypercapneicacidosis (due to failure to remove acid from tissue because of abnormalblood-flow), and in the case of the pregnant female, impairment ofblood-flow to fetus and severe hypoxemia in fetus.

SUMMARY OF THE INVENTION

One embodiment herein, denoted the first embodiment, is directed to amethod for negating or reducing decrease in blood-flow and/or hypoxemiain an abdominal organ which would otherwise have decreased oxygendelivery because of decreased blood-flow therein because of insufflatinggas being delivered into the abdominal cavity, comprising contactingsaid abdominal organ with a blood-flow to abdominal organ decreasepreventing agent in a therapeutically effective amount, preferablycomprising delivering the blood-flow to abdominal organ decreasepreventing agent into the abdominal cavity as part of a gas consistingessentially of the blood-flow to abdominal organ decrease preventingagent in a therapeutically effective amount and an insufflating gas. Theblood-flow to abdominal organ decrease preventing agent is preferablyethyl nitrite. The insufflating gas is a blood-flow decrease andhypoxemia causing insufflating gas and is typically carbon dioxide. Verypreferably, the gas consisting essentially of blood-flow to abdominalorgan decrease preventing agent and insufflating gas contains from 1 to1,000 ppm ethyl nitrite, e.g., 50 to 200 ppm ethyl nitrite. Gasinsufflation into the peritoneum also impairs fetal blood flow and ethylnitrite or other vasoditating gas can diffuse into the blood. to improvefetal blood flow and hypoxemia.

Pneumoperitoneum also impairs pulmonary function and raises bloodpressure and ethyl nitrite has been shown to improve pulmonary functionand can lower blood pressure.

The invention of the first embodiment involves a way to prevent orreverse with a drug a complication of a laparoscopic procedure and isanalogous to giving a patient a drug to raise blood pressure if bloodpressure drops during surgery. The invention of the first embodimenttreats a complication of laparoscopic surgery or diagnosis.

The invention of the first embodiment involves the treatment of mammals,including humans.

Another embodiment herein, denoted the second embodiment, is directed toa gas consisting essentially of insufflating gas and a blood-flow toabdominal organ decrease preventing agent in a therapeutically effectiveamount, e.g., ethyl nitrite used in amount of Ito 1,000 ppm, e.g., 50 to200 ppm.

The term “abdominal organ” is used herein to mean an organ in theabdominal cavity or retroperitoneum or a fetus or placenta.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of Time (hours) versus Doppler Flow Units and showsresults for effect on liver in respect to blood-flow in liver, of carbondioxide gas insufflation (15 mmHg for 1 hour) as determined in theexperiment of Example I and represents the current state-of-the-art.

FIG. 2 is a graph of Time (hours) versus Doppler Flow Units and showsresults for effect one liver in respect to blood-flow in liver, ofinsufflation with carbon dioxide gas containing 100 ppm ethyl nitrite asdetermined in the experiment of Example I and represents the invention.

FIG. 3 depicts graphs of relative blood-flow compared to baseline andshows effect on liver of carbon dioxide alone and of gas consisting ofcarbon dioxide and 100 ppm ethyl nitrite and shows results duringinsufflation and two hours post insufflation as determined in theexperiment of Example I. In FIG. 3, CO2 means CO₂ and E-NO means ethylnitrite.

DETAILED DESCRIPTION

We turn now to the embodiment herein, denoted the fast embodimentherein, which is directed to a method for negating or reducing decreasein blood-flow and/or hypoxemia in an abdominal organ which wouldotherwise have decreased oxygen delivery because of decreased blood-flowtherein because of carbon dioxide or other insulating gas, e.g., helium,argon or nitrogen, being delivered into the abdominal cavity, comprisingcontacting said abdominal organ with a blood-flow to abdominal organdecrease preventing agent in a therapeutically effective amount

The method is directed to use of a composition of matter in laparoscopicsurgery or in a laparoscopic diagnostic procedure, as a therapeuticagent.

Laparoscopic surgery allows surgery with minimal tissue injury andrelies on a miniature video camera and surgical instruments insertedinto the abdominal cavity usually through a small cut in the umbilicus.After an initial cut, a needle adapted to deliver insufflating gas isinserted. Then the insulating gas is delivered into the abdominal cavityto expand the abdominal cavity to enable better visualization andgreater workspace. The pressure resulting from the gas delivery normallyshould not exceed 15 mm Hg. The insufflating gas conventionally consistsof carbon dioxide. After sufficient expansion is obtained, a trocar isinserted through the umbilical cut. This is used for access to insertthe miniature video camera and surgical instruments. The video cameraprovides high resolution visualization and allows proper manipulation ofthe surgical instruments to carry out surgery effectively,

Diagnostic laparoscopy corresponds to laparoscopic surgery so far asinitial cut and insertion of insufflating gas is concerned but the videocamera is inserted to obtain diagnosis and surgery is not carried out.

Some texts available from Amazon.com in June, 2001 on laparoscopyinclude the following: Ballantyne, G. H., Atlas of Laparoscopic Surgery;Eubanks, S. (ed), et al, Mastery of Endoscopic and Laparoscopic Surgery;Pappas, T. N., Atlas of Laparoscopic Surgery; Beshoff, J. T., et al.,Atlas of Laparoscopic Retroperitoneal Surgery; MacIntyre, I. M. C.,Practical Laparoscopic Surgery for General Surgeons (8/94). The whole ofeach of these is incorporated herein by reference.

Surgery and diagnosis can be effected on abdominal organs within theperitoneum, e.g., on liver, or on opening of the peritoneum onretroperitoneal organs, e.g., kidneys and pancreas.

When the abdominal organs that are the subject of the laparoscopicprocedure, are within the peritoneum, e.g., liver, then organs withinthe peritoneum would otherwise have decreased blood-flow and arebeneficially acted by the invention herein. When the abdominal, organsthat are the subject of the laparoscopic procedure are retroperitoneal,then the retroperitoneal organs would otherwise have decreasedblood-flow and serum creatine increases associated with kidneydysfunction and are beneficially aided by the invention herein.

The application of the first embodiment of the instant invention tolaparoscopic surgery can be described as follows: In a method oflaparoscopic surgery wherein an insufflating gas is delivered into theabdominal cavity to enable better visualization and greater work space,the step is carried out of contacting the abdominal organs contactedwith the insufflating gas, with a blood-flow to abdominal organ decreasepreventing agent in an effective amount.

The application of the first embodiment of the instant invention to alaparoscopic diagnostic procedure can be described as follows: In amethod for laparoscopic diagnosis wherein an insulating gas is deliveredinto the abdominal cavity to enable better visualization, the step iscarried out of contacting the abdominal organs contacted with theinsufflating gas, with a blood-flow to abdominal organ, decreasepreventing agent in an effective amount.

The blood-flow to abdominal organ decrease preventing agents includeagents that cause blood vessel dilation or that increase blood-flow bydecreasing platelets or by decreasing neutrophil or red blood pluggingof vessels or by decreasing blood viscosity.

We turn now to the case of the first embodiment where the blood-decreasepreventing agent is caused to contact abdominal organs by delivering theblood-flow to abdominal organ decrease preventing agent into theabdominal cavity as part of a gas consisting essentially of theblood-flow to abdominal organ decrease preventing agent in effectiveamount and an insufflating gas.

We turn now to use of the gas. As in the case of conventionallaparoscopy, the pressure resulting from gas delivery should normallynot exceed 15 mm Hg. Within this framework, the amount of gas should besufficient to allow sufficient visualization and work space forlaparoscopy.

The gas can be delivered using a CO₂ insufflator equipped with apressure regulator.

As indicated above, the gas consists essentially of a blood-flow toabdominal organ decrease preventing agent in effective amount and theinsufflating gas.

We turn now to the blood-flow to abdominal decrease preventing agent.The decrease in blood-flow referred to as being prevented is that whichwould, except for the invention here, be caused by the insufflating gas.

When the blood-flow to abdominal organ decrease preventing agent isadministered as part of a gas, it must normally be a gas under theconditions of administration or must be converted to a gas foradministration. The agents should not have a boiling point such that thetemperature required to maintain them as gases in diluted form, i.e., incombination with insufflating gas, would harm an abdominal organ andpreferably should not condense in the abdominal cavity.

The blood-flow to abdominal organ decrease preventing agents which areadministered as part of a gas preferably have the formula RX-NO_(y)where R is either not present or is hydrogen/proton or C₁-C₇-alkyl and Xis oxygen, sulfur, nitrogen or metal selected, for example, from thegroup consisting of iron, copper, ruthenium and cobalt atoms or an alkylor alkenyl or alkylthio or alkenylthio group containing from 1 to 7,e.g., 1 to 6, carbon atoms which is straight chain or branched, or CF₃—or CF₃S—, and y is 1 or 2, excluding nitrous oxide. Specific treatingagents of the RX-NO_(y) class include, for example, ethyl nitrite (whichis the very preferred blood-flow to abdominal organ decrease preventingagent for use in the embodiments herein and is used is examples herein),methyl nitrite, tert-butyl nitrite, isoamyl nitrite,trifluoronitrosomethane (CF₃NO), CF₃SNO, CH₃SNO, CH₂═CHSNO, CH₂CHCH₂SNO,ONSCH₂—CH₂—CH₂SNO and CH₃CH₂CH₂SNO. Alkyl nitrites can be prepared asdescribed in Landscheidt et al. U.S. Pat. No. 5,412,147. Ethyl nitriteis available commercially, e.g., diluted in ethanol. CF₃NO is acommercial product or can be made by treatment of CF₃I with NO⁻ asdescribed in J. Phys. Chem. 100, 10641 (1996). Aliphatic thionitrites,i.e., compounds of the form RSNO where R describes an, alkyl or alkenylor hydrogen moiety, can be prepared by treatment of the correspondingthiol with a source of NO⁺ including, but not limited to, one or more ofthe following: tert-butyl nitrite, ethyl nitrite, nitrosoniumtetraftuoborate (NOBF₄), nitrosoniumperchlorate (NOClO₄), nitrosoniumhydrogen sulfate (NOHSO₄), nitrosonium hydrogen phosphate (NON₂PO₄), orHCl-acidified solutions of sodium nitrite.

Other blood-flow to abdominal organ decrease preventing agents for usein the embodiments herein, which are normally gases or which can beconverted into a gas for administration, include NOQ or QNO where Q ishalogen, e.g., Cl, Br or F, or hydrogen or NOQ or QNO generating agents,alkyl nitrososulfinates (RSO₂NO) where the alkyl group contains from 1to 10 carbon atoms, thionitrosochloronitrite (SOClONO), thionyldinitrite(SO(ONO)₂) and alkyl (including small peptides) thionitrites (RSNO₂)wherein the alkyl group contains from 1 to 10 carbon atoms or is smallpeptide, and nitrosourea.

Other blood-flow to abdominal organ decrease preventing agents for usein the embodiments herein, which are normally gases, are nitric oxide(NO), NO₂ and N₂O₃.

Still another blood-flow to abdominal organ decrease preventing agentfor use in the embodiments herein, which is normally a gas, is carbonmonoxide.

We turn now to cases of the first embodiment where the blood-flow toabdominal organ decrease preventing agent is not administered as part ofa gas.

The blood-flow to abdominal organ decrease preventing agents can beadministered as a dry powder or as a solution which is applied topicallyor nebulized on to an abdominal organ, such as a solution of an NO donor(an NO donor donates nitric oxide or a related species and moregenerally provides nitric oxide bioactivity, that is activity which isidentified with nitric oxide, e.g., vasolidation) such as a nitrosothiolor nitroglycerin or a calcium channel blocker such as verapamil.Suitable NO donors are described in “Methods in Nitric Oxide Research,”edited by Feelisch, M., and Stamler, J. S., John Wiley & Sons, New York,1996, at pages 71-115 and in Zapol U.S. Pat. No. 5,823,180 and in WO01/17596 published Mar. 15, 2001. Other blood-flow to abdominal organdecrease providing agents which can be administered in solutions includeprostaglandins E₁ and I. Other blood-flow to abdominal organ decreasepreventing agents which can be administered in solution or nebulized areangiotenisn enzyme inhibitors, e.g., captepril.

As indicated above, the blood-flow to abdominal organ decreasepreventing agent for use in the embodiments herein is used in atherapeutically effective amount. This is an amount that negates orreduces the blood-flow to abdominal organ decrease and relieves orreduces the resulting hypoxemia that without the instant invention wouldoccur, to extent of effecting blood-flow that is at least 5% of thatpresent in the organ if it were not contacted with insufflating agent,typically carbon dioxide, as measured by Doppler or tissue oxygenation.

In the embodiment where the blood-flow to abdominal organ decreasepreventing agent is administered as part of a gas, it typicallyconstitutes from 1 to 1,000 ppm, e.g., 50 to 200 ppm, of the gasconsisting essentially of insufflating gas, typically carbon dioxide,and blood-flow to abdominal organ decrease preventing agent.

The blood-flow to abdominal organ decrease preventing agent can beadmixed with carbon dioxide or other insufflating gas to provide a gasfor administration, e.g., by conventional gas blending methods.

Where the blood-flow to abdominal organ decrease preventing agent isadministered as a dry powder or as a solution, it can be administered inan amount which maintains patient's blood-flow to at least 5% of thatpresent in the abdominal organ before contact with insufflating gas asmeasured by Doppler or tissue oxygenation,

We turn now to the second embodiment herein, i.e., the gas consistingessentially of insulating gas, typically carbon dioxide, and ablood-flow to abdominal organ decrease preventing agent in atherapeutically effective amount. The blood-flow to abdominal organdecrease preventing agents axe those described above in conjunction withthe first embodiment herein. The effective amount is that describedabove in conjunction with the first embodiment herein. Very preferably,the gas consists essentially of carbon dioxide and from 1 to 1,000 ppm,e.g., 50 to 200 ppm, blood-flow to abdominal organ decrease preventingagent, very preferably ethyl nitrite. Admixture of the carbon dioxideand blood-flow to abdominal organ decrease preventing agent, can beeffected as described for the first embodiment.

The invention herein supported by or illustrated by the followingworking examples.

EXAMPLE I

Ten adult pigs were anesthetized at time zero using halothaneanesthetic. A small cut was made in the abdomen to allow access insidethe peritoneum. In the case of one group of five pigs, denoted group A,an insufflating needle was inserted, and starting at time 1 hour and 48minutes, an insufflating gas consisting of carbon dioxide was deliveredinto the abdominal cavity to standard operating pressure (of 15 mm Hg)and the insufflating gas was maintained in the abdominal cavity for 1hour whereupon the insufflating gas was removed by suction. In the caseof another group of five pigs, denoted group B, an insufflating needlewas inserted, and starting at time 1 hour and 35 minutes, aninsufflating gas consisting of carbon dioxide and 100 ppm ethyl nitritewas delivered to the abdominal cavity to standard operating pressure andthe insufflating gas was maintained in the abdominal cavity for about 1⅕hour whereupon the insufflating gas was removed by suction. In bothcases, blood-flow in liver was monitored by a laser Doppler flow method(a standard method where ultrasonic waves are projected at flowing bloodand bounce back) whereby blood-flow is determined starting at time 5minutes after time zero in the case of group A, and starting at abouttime 20 minutes after time zero in the case of group B and continuinguntil 2 hours after insufflating gas was removed. Results are shown inFIGS. 1-3. In FIGS. 1 and 2, the Doppler Flow Units are arbitrary units.In FIG. 3, the term “Relative Flow” means relative blood-flow in livercompared to baseline. FIG. 1 shows blood-flow results (flow in liver)for group A (carbon dioxide only). FIG. 1 illustrates that carbondioxide pneumoperitoneum produces a decrease in blood-flow to the liver,which was sustained even after the procedure was completed. FIG. 2 showsblood-flow results (flow in liver) for group B (carbon dioxide togetherwith 100 ppm ethyl nitrite). FIG. 2 shows that ethyl nitrite protectsagainst carbon dioxide induced decline in liver perfusion. FIG. 3 showsaverage values of blood-flow in liver for “Liver Insufflation,” that iswhile insufflating gas is present, and “Liver Post-Insufilation,” thatis 2 hours after insufflating gas is removed. FIG. 3 shows about 70%more blood-flow in the ethyl nitrite case during insufflation and about40% more blood-flow in the ethyl nitrite case 2 hours post-insufflation.The same protection by ethyl nitrite against renal dysfunction ispredicted where the peritoneum is opened.

EXAMPLE II

A 23-year-old black female, 32 weeks pregnant, undergoes laparoscopicevaluation for right lower quadrant pain. Thirty minutes into theprocedure, fetal PO₂, measured by an electrode placed on the head, is 7mmHg. 100 ppm ethyl nitrite is added to the carbon dioxide insufflatinggas, and the fetal PO₂ increases to 25 mm Hg.

EXAMPLE III

A 70-year-old male undergoes laparoscopic cholecystectomy. One hour intothe procedure, liver function tests start to rise and the patientcomplains of abdominal pain suggestive of intestinal ischemia. Ethylnitrite 100 ppm is added to the insulating gas with resolution ofabdominal pain.

EXAMPLE IV

A 55-year-old woman with renal artery stenosis undergoes laparoscopyappendectomy and diagnostic evaluation of a renal mass. Because ofconcerns regarding decreased renal perfusion, 100 ppm ethyl nitrite isadded to insufflating gas and protects against decrease in blood-flow.

EXAMPLE V

A sixty-year-old white female undergoes laparoscopic appendectomy.Because of concerns of impaired renal function, pulmonary function andhypertension, nitroglycerin (3 cc of 100 micromolar) is nebulized intothe abdominal cavity. Blood pressure increases are prevented andpulmonary and renal functions are kept stable.

VARIATIONS

Variations of the above will be obvious to those skilled in the art.Thus, the scope of the invention is defined by the claims.

1. A method for negating or reducing decrease in blood flow in anabdominal organ which would otherwise have decreased oxygen deliverybecause of decreased blood-flow therein because of being contacted withinsufflating gas, comprising contacting said abdominal organ with ablood-flow to abdominal organ decrease preventing agent in atherapeutically effective amount.
 2. The method of claim 1 where thestep of contacting said abdominal organ with a blood-flow to abdominalorgan decrease preventing agent in a therapeutically effective amountcomprises delivering the blood-flow to abdominal organ decreasepreventing agent to the abdominal cavity as part of a gas consistingessentially the blood-flow to abdominal organ decrease preventing agentin therapeutically effective amount and an insufflating gas.
 3. Themethod of claim 2 where the insufflating gas is carbon dioxide.
 4. Themethod of claim 3 where the blood-flow to abdominal organ decreasepreventing agent is ethyl nitrite.
 5. The method of claim 4 where thegas contains from 1 to 1,000 ppm ethyl nitrite.
 6. The method of claim 5where the gas contains from 50 to 200 ppm ethyl nitrite.
 7. The methodof claim 1 where the amount of blood-flow to abdominal organ decreasepreventing agent is effective to relieve hypoxemia
 8. The method ofclaim 1 where the blood-flow to abdominal organ decrease preventingagent is administered as a nebulized dry powder or as a solution.
 9. Agas consisting essentially of insulating gas and a blood-flow toabdominal organ decrease preventing agent in a therapeutically effectiveamount.
 10. The gas of claim 9 where the insullating gas is carbondioxide and the blood-flow to abdominal organ decrease preventing agentis ethyl nitrite.
 11. The gas of claim 10 containing 1 to 1,000 ppmethyl nitrite.
 12. The gas of claim 11 containing 50 200 ppm ethylnitrite.